Process for the preparation of 17-substituted-delta4-gonenes and intermediates

ABSTRACT

WHEREIN R represents a member selected from the group consisting of hydrogen and the acyl of an organic carboxylic acid having from one to 18 carbon atoms, R&#39;&#39; represents an alkyl having from one to four carbon atoms, Riv represents a member selected from the group consisting of lower alkyl, lower alkenyl or lower alkynyl, and B represents a member selected from the group consisting of two hydrogens in the 9 Alpha and 10 Beta position and a double bond which comprises the steps of reacting a 3ketal-4,5-seco-gonane-5-one with a ketalizing agent, oxidizing the resultant 3,5-diketal-4,5-seco-gonane-17 Beta -ol, reacting the resultant 3,5-diketal-4,5-seco-gonane-17-one with an organometallic compound, hydrolyzing the resultant 3,5-diketal17 Alpha -Riv-4,5-seco-gonane-17 Beta -ol, cyclizing the resultant 17 Alpha -Riv-4,5-seco-gonane-17 Beta -ol-3,5-dione and recovering said Delta 4-gonenic steroid. The novel intermediates are also part of the invention. The Delta 4-gonenic steroids are known compounds having steroidal properties.   A process for the production of a Delta 4-gonenic steroid having the formula

United States Patent 1 Warnant et al. 7

I 1 PROCESS FOR THE PREPARATION OF 17-SUBSTITUTED-A4-GONENES ANDINTERMEDIATES [75] Inventors: .lulien Warnant, Neilly-sur-Seine,

Jean Jolly, Clichy-sousBois; Robert Joly, Montmorency, all of France[73] Assignee: Roussel Uclaf, Paris, France 22 Filed: June 29,1972 [21]Appl. No.: 267,364

Related US. Application Data [60] Division of Ser. No, 63,277, Aug. 12,1970, Pat. No.

3,702,334, which is a continuation-inpart of Ser. No. 640,507, May 23,1967, Pat. No. 3,591,606.

[52] US. Cl 260/340.9, 260/410, 260/476, 260/488, 260/586, 424/278,424/298, 424/331 [58] Field of Search 260/3409 [56] References CitedUNITED STATES PATENTS 3,117,979 1/1964 Nomine et a1. 260/3409 FOREIGNPATENTS OR APPLICATIONS 1,003,086

9/1965 Great Britain 260/3409 Primary Examiner-Donald G. Daus AssistantExaminerMary C. Vaughn Attorney, Agent, or F irm-Hammond & Littell [57]ABSTRACT A process for the production of a A gonenic steroid having theformula 1 Oct. 22, 1974 3,5-diketal-4,5-seco-gonane-17-one with anorganometallic compound, hydrolyzing the resultant 3,5- diketal-17a-R"'-4,5-seco-gonane-173-01, cyclizing the resultant 17a-R"-4,5-seco-gonane-17/3-ol-3,5-dione and recovering said N-gonenicsteroid. The novel intermediates are also part of the invention. The Agonenic steroids are known compounds having steroidal properties.

5 Claims, No Drawings PROCESS FOR THE PREPARATIONOF17-SUBSTITUTED-A4-GONENES any INTERMEDIATES REFERENCE TO PRIORAPPLICATIONS THE PRIOR ART It is a well known fact that the preparationof l9-nor steroids substituted in the l7-position presents difficultproblems due to the presence'of the functions on the steroid moleculeapt to be attacked'at the very moment of the introduction of the desiredsubstituent in the 17- position. This is the case, in particular, withsteroids having a ketone function in the 3-position and/or double bondin the 4,5-position.

Moreover, it is known that in the former processes for the preparationof steroid derivatives by means of total synthesis, the authors have, asa rule, preferred to complete the construction of the steroid skeletonfirst, and only then to proceed with the substitution in the 17-position(see, for example, Velluz et al., Recent Advances in the Total Synthesisof Steroids, Agnew. Chem. Intern, Edit., Vol. 4 [1965] No. 3).

OBJECTS OF THE INVENTION An object of the present-invention is thedevelopment of a process to form a steroid substituted in thel7-position from a steroid intermediate which can 'undergo substitutionin the l7-position and thereafter total synthesis steps.

Another object of thepresent invention is the development of a processfor the production of a A -g'onenic steroid of the formula 1s 1 Riv 1 Yv z wherein R and R have the above-assigned meanings, Z 18 a memberselected from the group consisting of oxygen,

and R',

wherein R" .is lower alkyl and R' is selected from the group consistingof lowerv alkylene and substituted llower alkylene, and A is selectedfrom the group conwhere X is a member selected from the group consistingof and R W OR 0 wherein R and R have the above-assigned mean ings, R andA have the above-assigned meanings, and R is the acyl of an organiccarboxylic acid having from 'one to 18 carbon atoms, by the action of analkaline saponifying agent, (3) oxidizing the resultant 3,5-diketals of4,5 -seco-gonane-l7B ol-3,5-diones of the formula fl, 'oH f D wherein R,X and A have the above-assigned meanings by the action of an hydroxyloxidizing agent, (4) reacting the resultant 3,5-diketals of4,5-seco-gonane- 3,5,l7 triones of the formula wherein R, X and A havethe above-assigned meanings with an organometallic compound of theformula selected from theroup consisting of R"Li and R MgX,

wherein R hast e above-assigned meaning and X represents a halogen, (5)recovering the resultant 3,5-

diketals of l7a-R"-4,5-seco-gonane-3,5-diones of the formula wherein, R,R, R", X and A have the above-assigned meanings, (6) hydrolyzing saidcompounds by the action of a ketal hydrolyzing agent in the presence ofan organic solvent, (7) subjecting the resultant l7a-R"-4,5-seco-gonane-3,5-diones of the formula wherein R, R, R and A have theabove-assigned meanings to the action of a cyclizing agent selected fromthe group consisting of acid and basic cyclization agents, and (8)recovering said A gonenic steroid.

A further object of the present invention is the obtention of the novelintermediates: the 3,5-diketals of 17a- R'-4,5-seco-gonane-3,5-diones;and the l7a-R'-4,5- seco-gonane-3,5 -diones.

These and other objects of the present invention will become moreapparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION It has now been discovered that a novelclass of intermediate products for the synthesis of steroid derivatives,namely, the 3,5-diketals of l3/3-alkyl-4,5-secogonane-3,5,l7-triones ofthe general formula given in the above, permit, in contrast to the3-monoketals already known, to bypass the difficulties previously metwith in the preparation of l9-nor steroids substituted in the 17position, due to the possibility of introducing at this stage thedesired substituents in the 17 position.

The 3,5-diketals of the l3,B-alkyl-4,5-seco'gonane- 3,5, l 7-trionesthus formed shown in neutral or alkaline medium an excellent stabilitywith regard to the functions in the 3 and positions, which facilitatesthe possible conversions in the 17 position. Moreover, they are, aftersplitting off the ketal functions in the 3 and 5 positions, easilycyclized by the usual agentsto give the tetraacyclic steroid skeleton.

The present invention relates to a new class of intermediate productsfor the synthesis of steroid derivatives as well as to a process for thepreparation of these products.

More particularly, the invention relates to the 3,5- diketalsof thel3/3-alkyl-l7a-R l7l3-QR-4,5-secogonane-3,5-diones of the generalformula I Riv wherein, here and in the following, R represents hydrogenor the acyl of an organic carboxylic acid having one to 18 carbon atoms,R is an alkyl radical containing one to four carbon atoms, X representsthe group R" being a lower alkyl, or X represents the group R' being aloweralkylene radicai, substituted or unsubstituted, R" represents loweralkyl, lower alkenyl or lower alkynyl, and the dashed line represents apossible 9'( l l double bond; and the 13B-'alkyl-l7a-R'-l 7,8-OR-4,5-se'co'-gonane-3,S-diones of the general formula II wherein R, Rand R have the above-assigned meanings.

The process for the preparation of N-gonenic steroids of the generalformula III, also object of the pres- III 'wherein R, R and R have theabove-assigned mean ings and B is a double bond or two hydrogen in the9a and 10/3 position, is characterized in that a 3-Z-l3B-alkyl-l7B-OR-4,S-seco-gonane-S-one of the general formula IV whereinZrepisa't'sak'emne oii gen orX, R and X having the above-assignedmeanings, and the dashed line represents a possible 9(l0) double bond,is subjected to the action of a ketalization agent, the diketal obtainedof the general formula V wherein X, R, R and the dashed line have theaboveassigned meanings, when R represents the radical of an organiccarboxylic acid having from one to 18 carbon atoms, is saponified, andthe diketal of the general formula VI x x v1 wherein X, R and t hddashedline have the aboveassigned meanings, is reacted with an oxidizingagent. The resulting 3,5-diketal of 13B alkyl-4,5-seco-gonane-3,5,17-trion e"of the general formula VII wherein R and X have theabove-assigned meanings, is isolated.

The process, also object of the invention, can be advantageouslyexecuted as follows:

A. The ketalization agent is chosen from the group consisting of thelower cyclic ketals, the lower noncyclic ketals and the lower alkanols.The work is conducted in the presence of an acid catalyst.

B. The cyclic ketals are chosen from the group consisting of2-methyl-2-ethyl-dioxolane, 2-methyl-2-phenyl-dioxolane,2-methyl-4-(6-methylbenzyl)- dioxolane,2,2-di-methyl-4-(fi-methylbenzyl)- dioxolane, 2-chloromethyldioxolane,Z-(B-chloro)- ethyl-dioxolane and Z-(B-bromo)-ethyl-dioxolane.

C. The non-cyclic ketals are selected from the group consisting of thedimethyl ketalof acetone, the diethyl ketal of acetone, the dimethylketal of Z-butanone, the dimethyl ketal of dimethylformamide and thediethyl ketal of dimethylformamide.

D. The aliphatic alcohols employed as ketalizing agents are chosen fromthe group consisting of glycols such as lower alkanediols, for example,ethyleneglycol, l,3-propane-diol, 2,2-dimethyl'l ,3-propanediol, and oflower alkanols such as methanol or ethanol.

E. The saponification of the 3,5-diketal ofl3B-alkyll7B:acyloxy-4,5-seco-gonane-3,5-dione of the general formula Vis effected by an alkaline agent such as an alkali metal hydroxide, forexample, sodium or potassium hydroxide. The work is carried out in alower alkanol'such as methanol or ethanol.

F. The oxidation of the hydroxyl in the 17 position is realizedaccording to the Oppenauer method bymeans ofa lower aliphatic ketonesuch as lower alkanones, for example, acetone, methylethyl ketone,methylisobutyl ke'toneor lower cycloalkanones, for example,cyclohexanone, in the presence of an aluminum tertiary lower alkanolatesuch as aluminum isopropylate.

G. The oxidation of the hydroxyl in the 17 position is effected byusing, as oxidizing agent, chromic acid anhydride in pyridine.

As it has already been mentioned, the advantages of the novel compoundsof the general formula Vll lie in .particular in the fact that theyallow an easy preparation of l9-nor steroids substituted in the 17position, as

' it will be explained in the following.

The introduction of a substituent in the 17a position is realized, forexample, by reaction of a compound of formula I with an organometalliccompound of the type R 'Li or R'MgX (X being a halogen and, inparticular, bromine or iodine and R" represents a hydrocarbon radical,preferably lower alkyl, lower alkenyl or lower alkynyl). g

In the particular case of ethynylation, this reaction may be realizedwith the aid of an ethynyl magnesium halide or also with the aid of analkali metal acetylide or also with the aid of acetylene while operatingin the presence of tertiary 'alcoholates or amides of alkali metalsoralkaline earth metals.

The introduction of the ethyl or vinyl radical in the 17d position canbe effected with excellent yields in an indirect fashion in two steps.By ethynylation of the ketone in the 17 position and subsequentreduction of the ethynyl radical by hydrogenation in the presence of acatalyst having a platinum or palladium base, the 17aethyl derivative isobtained, whereas if the reduction is arrested after the absorption of amole equivalent of hydrogen gas, the l7a-vinyl derivative is obtained.

The process of indirect introduction may furthermore be significant withregard to the preparation of the l7a-propyl derivatives. In that case,allyl magnesiumbromide can be reacted with a compound of for- 'mula I,then the resultant allylic derivative is subjected to a hydrogenation inthe presence of a catalyst having a platinum or palladium base.

The 3,5-diketals of the l3B-alkyl-17a-R"-l7,8-hydroxy-4,5-seco-gonane-3,S-diones, possibly having a double bond in the9(1 1) position. (I, R=H), obtained by the above reactions, can beesterified in the 17 position with an organic carboxylic acid havingfrom one to 18 carbon atoms by employing the usual acylation agents suchas the corresponding acid, its anhydride or its chloride.

Such acids are the aliphatic or cycloaliphatic carboxylic acids,saturated or unsaturated, or the aromatic or heterocyclic carboxylicacids, for example, the alkanoic acids such as formic, acetic,propionic, butyric, isobutyric, valeric, insovaleric, trimethylacetic,caproic, B-trimethylpropionic, enanthie, caprylic, pelargonic, capric,undecylic, lauric, myristic, palmitic, stearic, etc., the alkenoic acidssuch as undecylenic, oleic, etc., the cycloalkyl carboxylic acids suchas cyclopentyl-, cyclopropyl-, cyclobutyland cyclohexylcarboxylic acids,the cycloalkylalkanoic acids such as cyclopropylmethyl carboxylic acid,cyclobutylmethyl carboxylic acid, cyclopentylethyl carboxylic acid,cyclohexylethyl carboxylic acid, the cyclopentylacetic,cyclohexylacetic, or propionic acids, the phenylalkanoic acids such asphenylacetic or propionic acids, benzoic acid, the phenoxyalkanoic acidssuch as phenoxyacetic acids, p-chlorophenoxyacetic acid,2,4-dichlorophenoxyacetic acid, 4-tert.-butyl- 'phenoxyacetic acid,3-phenoxypropionic acid, 4

7 hydroxy-4,5-seco-gonane-3,5-diones with or without a 9(1 1) doublebond, whether esterified or unesterified in the 17/3 position, can besubsequently converted into tetracyclic steroids.

For that purpose, such a 3,5-diketal of a 13B-Rl7a- R-l 7B-hydroxyorl7B-acyloxy-4,5-seco-gonane-3,5- dione formed as indicated above is'subjected to a ketal hydrolysis in the presence of an acid, such ascitric, acetic, hydrochloric or sulfuric acid, and in the presence ofone or several solvents such as an alcohol, for example, the methanol orethanol, and a hydrocarbon such as benzene or toluene. in the manner theketone in the 3 and 5 positions are regenerated and the corresponding3,5-dioxo derivative is recovered possibly having a double bond in the9(10) position. Next, this 3,5-dioxo derivative is subjected to theaction of a basic cyclization agent such as an alkali metal alcoholate,or to the action of an acid cyclization agent such as hydrochloric acidor 'the hydrochloric acid-acetic acid mixture; I

Thus, a tetracyclic steroid of the general formula lll wherein R, R andR have the previous meanings, is

III

obtained possibly with a double bond in the 9( l0) posi-.

tion.

In the case where the cyclization agent is a secondary base such as, forexample, pyrrolidine, the corresponding enamines are obtained in the3-position, which by means of acid hydrolysis supply the above-indicated3- oxo-A or 3-oxo-A derivatives.

with the compounds of formula IV.

The starting compounds of the process of the invention are described andare accessible by application of the processes of French Pat. Nos.1,243,000, 1,364,556, 1,476,509 and 1,432,569.

The following examples will serve for better comprehension of theinvention.'However, it is to be understood that they are not to bedeemed limitative in any degree. The process described in the followingcan also be applied withthe same readiness to the 13B-ethyl, l3B-propylor l3B-butyl derivatives as to the 133- methyl derivatives. v 1

EXAMPLE 1 Preparation of 3-ethylenedioxy-4,5-seco-estranel 7/3-ol-5-one900 cc of toluene, 18 cc of pyridine, 180 gm of 3- 8ethylenedioxy-4,5-seco-A -estrene-l7B-ol-5-one and 72 gm of palladizedtalc containing 2 percent of palladium, were introduced into ahydrogenation vessel. The vessel was purged and the mixture was agitatedunder an atmosphere of hydrogen at room temperature. Over a period of 6hours about 12 liters of hydrogen were absorbed.

Thereafter, the reaction solution was filtered and 180 cc of water wereadded thereto. Next, the washing was effected, followed by decanting,first-with an aqueous solution of normal sulfuric acid to eliminate thepyridine, then with an aqueous solution of sodium bicarbonate andfinally with water until the wash waters were neutral. The toluene phasewas dried over magnesium sulfate, concentrated to dryness under reducedpressure, thus obtaining 180 gm of raw 3-ethylenedioxy-4,5-seco-estrane-17B-ol-5-one. This product was used assuch for the next step.

A sample of this product was purified for analysis by recrystallizationfrom isopropyl ether containing 1 part per thousand of pyridine, thenfrom ethyl ether containing 1 part per thousand of pyridine. It had amelting point of to C and a specific rotation [a] +3 1: 1 (c 1 percentin methanol containing 1 percent of pyridine), and it possessed thefollowing characteristics: I Analysis: C H O4; molecular weight 336.46Calculated: C 71.39% H 9.59%

Found: 71.2 9.5

infrared spectra (in chloroform):

Absorption at:

1,704 cm: carbonyl 3,600 cm: hydroxyl and'C-O-C band, characteristic ofthe ketal function. This product is not described in the literature.

The 3-ethylenedioxy-4,5-seco-A -estrene-173-01- 5-one, utilized as thestarting product in the preceding preparation, was obtained in thecourse of the process described in French Pat. No. 1,364,556.

In an analogous manner, the3-ethylenedioxy-l3fiethyl-4,5-seco-gonane-l7B-ol-5-one was prepared bystarting with the 3-ethylenedioxy-l3B-ethyl-4,5-seco- A-gonene-l7B-ol-5-one, having a melting point of to C, this product beingobtained in the course of the process described in the French Pat. No.1,476,509. The 3-ethylenedioxyl 3B-ethyl-4,5-secogonane-l7B-ol-5-one isnot described in the literature.

EXAMPLE ll Preparation of 3 ,S-bis-(ethylenedioxy )-4,5-seco-estranel7-one Step A:

Preparation of 3,5-bis-(ethylenedioxy)-4,5-secoestrane- 1 78-01.

Under an inert atmosphere, first 70 gm of 3-ethylenedioxy-4,5-seco-estranel7Bol-5-one, then 0.35 gm of paratoluenesulfonic acid were introduced into 350 cc of methylethyldioxolane. Themixture was agitated for about 15 hours. Thereafter, the reactionmixture was made alkaline with 2.1 cc of pyridine, agitated for 10minutes, then 126 cc ofwater and 14 cc of a saturated aqueous solutionof sodium bicarbonate was added. The organic phase was separated bydecanting and washed with water. The aqueous wash waters were extractedwith benzene, which was washed with water, than combined with theorganic phase previously isolated and washed. These combined organicphases were dried over magnesium sulfate and concentrated to drynessunder reduced pressure. The residue was taken up in isopropyl ether andconcentrated to dryness under reduced pressure. 84 gm of a raw productwere recovered, which was crystallized from isopropyl ether, obtaining69.7 gm of 3,5'bis- (ethylenedioxy)-4,5-seco-estrane-17,8-01.

The product had a specific rotation [a] =+18 i 1 (c 1 percent inmethanol containing 1 percent of pyridine).

By concentration of the mother liquors resulting from thecrystallization, a second yield of product was obtained.

A sample of the product was purified for analysis from isopropyl ethercontaining 1 part per thousand of pyridine. it had a melting point of 90to 100C and a specific rotation [a] +19 i 1 (0 1 percent in methanolcontaining l percent of pyridine), and possessed the followingcharacteristics:

Analysis: C H O molecular weight 380.50 Calculated: C 69.44% H 9.53%

Found: 69.1 9.7

infrared spectra (in chloroform):

Absorption at 3,600 cm": hydroxyl.

and C-O-C band characteristics of the ketal function.

This product is not described in the literature/ Step B:

Preparation of 3,5-bis-(ethylenedioxy)-4,5-secoestranel 7-one Under aninert atmosphere, 40 gm of purified 3,5-bis-(ethylenedioxy)-4,5'seco-estrane-17l3-ol were dissolved in a mixture of400 cc of toluene and 80 cc of methylethylketone in a 2-liter vesselequipped with an agitation means and a descending condenser. Thesolution was brought to boiling point under agitation. Then afterdistillation had been established, a solution of 14.4 gm of aluminumisopropylate in 540 cc of toluene and 720 cc of methylethylketone wasintroduced. This addition was effected as follows: The two reactantswere introduced simultaneously at regular intervals for about minutesand withina total tare of' tftb shears in such a manner that theevaporated solvent volume v was proportionately compensated by theaddition of the two reactants. Thus, within a space of about 4 to 5hours, 1,260 cc of distillate was recovered. The distillation wascontinued until 80 cc of distillate were recovered. The reaction mixturewas cooled. Next, 36 cc of water were introduced and the solution wasagitated. The precipitated alumina was vacuum filtered. Water was addedto the filtrate and the organic solvents were eliminated by steamdistillation. The aqueous mixture was cooled and the precipitateformedwas vacuum filtered, washed with water and dried. The recoveredraw product was crystallized from methanol containing 1 part perthousand of pyridine, thus obtaining 30.8 gm of3,5-bis-(ethylenedioxy)-4,5-seco-estrane-17-one. The product had amelting point of 1 14C.

A sample of this product, purified for analysis by crystallization firstfrom isopropyl ether containing 1 part per thousand of pyridine, thenfrom methanol containing l part per thousand of pyridine, had a meltingpoint of 1 14C. and a specific rotation '[a] +75 i 115 (c= l percent inmethanol containing 1% of pyridine), and had the followingcharacteristics:

Analysis: C H -,,O,-,; molecular weight 378.49

Calculated: C 69.81% H9.05%

Found: 69.9 8.9

Infrared spectra (in chloroform):

Absorption at 1,732 cm: carbonyl and C-O-C band characteristic of theketal function.

This product is not described in the literature.

- EXAMPLE Ill Preparation of3,5-bis-(ethylenedioxy)-4,5-seco-estrane-17-one,

starting with 4,5 seco-estrane-17B-ol-3,5-dione 10 gm of4,5-seco-estrane-l7B-ol-3,5-dione, a product described in French Pat.No. 1,432,569, were introduced into 60 cc of methylethyldi-oxlane. Themixture was brought to reflux under an inert atmosphere and 1 volume ofsolvent was distilled therefrom under normal pressure. The mixture wasthen cooled toward C and 0.050 gm of paratoluene sulfonic acid wasadded. Under a slight vacuum, the mixture was distilled for 3 hours atabout 75C., recovering about 10 cc of distillate per hour andmaintaining the reaction media at a constantvolume by the addition ofmethylethyldioxolane. Thereafter, the methylethyldioxolane waseliminated under reduced pressure. The reaction media was cooled. 20 ccof benzene and 0.4 cc of pyridine were added to the reaction mixture,which was then homogenized and was, after 18 cc of water and 2 cc of asaturated solution of sodium bicarbonate had been added,

agitated for 10 minutes. The benzenic phase was separated by decantingand washed with water. The aqueous phases were re-extracted withbenzene. After having been washed with water, these benzenic re-extractswere combined with the principal benzenic solution. After the additionof one drop of pyridine, the whole of the combined benzenic solutionswas concentrated to dryness under reduced pressure. The resultantresidue was dissolved in hot ethyl ether. The ether was expelled undervacuum and the crystallizate was dried. 13.27 gm of a raw product wereobtained, having a melting point of to C and a specific rotation [or]+18 1 (c 1 percent i n methanol containing 1 percent of pyridine). 1

This raw product was recrystallized from iso-propyl ether containing 1part per thousand of pyridine, thus obtaining 8.75 gm of3,5-bis-(ethy11enedioxy)4,5-secoestrane-l7B-ol, having a melting pointof 90 to 100C. with a specific rotation of [a] +19.5 i 1 (c 1 percent inmethanol containing 1 percent of pyridine). This product was identicalto the 3,5-bis- (ethylenedioxy)-4,5-seco-estrane-17B-ol prepared in StepA of the preceding example. By applying the pro cess described in Step Bof the preceding example to this compound,3,5-bis-(ethylenedioXy),-4,5-secoestrane-17-one was obtained, which wasidentical to the product prepared according to Example 11.

EXAMPLE 1V Preparation of 3,5-bis-(ethylene dioxy)-4,5seco- A estrene- 17.-one

Step A:

Preparation of 3,5-bis-(ethylenedioxy)-17B- benzoyloxy-4,5-seco-A""-estrene.

Under an atmosphere of nitrogen, 2 gm of 173- benzoyloxy-4,5-seco-A-estrene-3,5-dione, having a specific rotation [01] ==+43 (c= 1 percentin methan01), a product described in French Pat. No. 1,243,000, wereintroduced into 60 cc of methylethyldioxolane. 0.06 gm of paratoluenesulfonic acid monohydrate were added thereto, and the reaction mixture 1l was heated under agitation in order to obtain within the space of 5hours a volume of distillate of about 20 cc while maintaining thereaction volume constant by the regular addition ofmethylethyldioxolane. The pH was adjusted to 8.0 by the addition of anaqueous solution of sodium bicarbonate. The organic phase was separatedby decanting; washed with water until neutrality was attained and dried.One drop of pyridine was added to the organic phase, which was thendistilled to dryness under reduced pressure. Next, ethanol was added tothe residue and the mixture was again concentrated to dryness underreduced pressure.

The resultant residue was crystallized from ethanol, thus obtaining 1.6gm of 3,5-bis-(ethylenedioxy)-17B- benzoyloxy-4,5-seco-A -estrene. Theproduct had a melting point of 165 to 166C.

A sample of this product, recrystallized first from isopropyl ether inthe presence of pyridine, then from ethanol also in the presence ofpyridine, had the following constants:

Melting point 166 to 167C Specific rotation [01] +23.2 (c 0.9 percent inmethanol). V

Analysis: C H O molecular weight 482.6 Calculated: C 72.17% H 7.93%

Found: 72.4 8.1

Ultraviolet spectra (in ethanol):

max. at 230 ma 6 14,300

max. at 273 mp/e 910 max. at 280 mp. e 720 This product is not describedin the literature. Step B:

Preparation of 3,S-bis-(ethylenedioxy)-4,5-seco- A -estrene- 1 7,8-01

Under an atmosphere of nitrogen, 600 mg of 3,5-bis(ethylenedioxy)-17B-benzoyloxy-4,5-seco-A estrene were introduced into19 cc of a 0.158 N potassium hydroxide solution. The mixture wasmaintained at reflux for 1 hour, then concentrated to dryness underreduced pressure. Next, water was added to the mixture, which was thenextracted withether and the extracts ,were combined. The organicsolution obtained was washed with water, dried and concentrated todryness. After adding isopropyl ether, the solution was crystallized,vacuum filtered and dried. in this manner, 362 mg of 3,5-bis-(ethylenedioxy)-4,5-seco-A estrene- 1 7,8-01 were obtained having amelting point of 130C.

A sample of this product was purified by crystallization first fromisopropyl ether, then from petroleum ether (boiling range 60 to 80C).The product had a melting point of 132C and a specific rotation [(11+25.8 (c 0.7 percent in methanol).

Analysis: C H O molecular weight 378.49 Calculated: C 69.81% H 9.05%Found:' 69.8 9.1

This product is not described in the literature. Step C1 Preparation of3.5-bis-(ethylenedioxy)-4,5-seco- A -estrene-17-one Within a space ofminutes, about 1 gm of chromic acid, followed by a solution composed of10 cc of pyridine and 1 gm of 3,5-bis-(ethylenedioxy)-4,5-seco- Nl-estrene-flfi-ol were introduced into 10 cc of pyridine cooled to 0C.This mixture was allowed to warm to a temperature of 20C., then agitatedfor hours at this temperature. Thereafter, the reaction mixture waspoured into water and filtered. The aqueous phase was extracted withmethylene chloride and the methylene chloride extracts were combined.The organic solution obtained was washed with water and dried. thenconcentrated to dryness under reduced pressure.

The residue was crystallized from isopropyl ether and 0.665 gm of3,5bis-(ethylenedioxy)-4,5-seco-A"- estrenel 7-one was obtained, havinga melting point of 98C.

A sample of this product was purified for analysis by crystallizationfrom isopropyl ether. It had a melting point of 98C. and a specificrotation [a] +l05 (c 0.5 percent in methanol). Analysis: C H O molecularweight 376.46 Calculated: C 70.18% H 8.56% Found: 70.1 8.5

This productis not described in the literature.

' EXAMPLE V Preparation of 17a-ethynyl-19-nor-testosterone Step A:

Preparation of 3,5-bis-(ethylenedioxy)-17a-ethynyl- 4,5-seco-estrane- 176-01 Under agitation, a stream of acetylene was allowed to bubblethrough 40 cc of a sodium tert.-amylate solution in toluene containing2.28 gm of sodium per cc for 2 hours. Thereafter, 5 gm of3,5-bis-(ethylenedioxy)- 4,5-seco-estrane-17-one (described in Step B ofExample 11) and 10 cc of toluene were introduced into the solution ofsodium acetylide obtained. The mixture was then agitated for 3 hours and30 minutes at room tem perature while a stream of acetylene was bubbledtherethrough. Next, the reaction mixture was cooled to about 15C. underan inert atmosphere. A solution of 5 gm of ammonium'chloride in 15cc ofwater was introduced. The toluene was distilled under reduced pressurewhile maintaining the volume constant by addition of water, thusobtaining 5.28 .gm of 3,5-bis-(ethylenedioxy)-17a-ethynyl-4,5-seco-estrane-1 78-01.

The product had a melting point of 181 to 182C. and was utilized as suchfor the next step.

A sample of this product, purified for analysis by recrystallizationfrom methanol containing 1 part per thousand of pyridine, had a meltingpoint of 183C. and a specific rotation [a] 30 2 (c 1 percent in methanolcontaining 1 percent of pyridine) and possessed the followingcharacteristics: Analysis: C H O molecular weight 404.52 Calculated: C71.25% H 8.97% Found: 71.4 9.0 lnfrafred spectra (in chloroform):Absorption at:

3,300 cm": ethynyl 3,590 cm": hydroxyl and C-O-C band characteristic ofthe ketal function.

This product is not described in the literature.

' Step B:

Preparation of 17a-ethyny1-4,5-seco-estrane1 7,8-01- 3,5-dione First,1.5 gm of 3,5-bis-(ethylenedioxy)-l7a-ethynyl- 4,5-seco-estrane- 173-01, then 1.5 gm of citric acid were introduced into a mixture of 7.5cc of toluene, 3 cc of methanol and 3 .cc of water. Under agitation andan inert atmosphere, the mixture was held at reflux for one hour. Then15 cc of water were added thereto. The toluene was concentrated underreduced pressure. The precipitate formed was isolated by being vacuumfiltered, washed with water until the wash waters were l 13 neutral anddried. Thus, 1.13 gm of l7a-ethynyl-4,5- seco-estrane-l7B-ol-3,5-dionewere obtained. The product had a melting point of 135 to 136C. and itwas utilized as such for the following step.

A sample of this product, purified for analysis by crystallization fromethyl ether, had a melting point of 135 to 136C. and a specific rotation[a] 50.4 2 (c 1 percent in methanol) and had the followingcharacteristics:

Analysis: cg Hgfi lli molecular weight 316.42 Calculated: C 75.91percent H 8.91 percent Found: 76.0 8.9 a

infrared spectra (in chloroform):

' Absorption at:

1,703 cm": carbonyl 3,300 cm: ethynyl 3.590 cm":'hydroxyl This productis not described in the literature. StepC:

Obtention of l7a-ethynyl-l9-nor-testosterone Under an inert atmosphere,0.900 gm of 17a ethynyl-4,5-seco-estrane-17B-ol-3,5-dione wereintroduced into a mixture of 9 cc of methanol and 2.7 cc of methylenechlorideThe mixture was agitated fo'r'l5 minutes; then 1 cc of amethanolic solution of sodium methylate, containing 7.8 gm of sodium per100 cc, was added, and the reaction mixture was' agitated for hours atroom temperature. Thereafter, 0.3 cc of acetic acid and 10 cc of waterwere addedNext, the methanol and the methylene chloride were eliminatedunder reduced pressure, and the precipitate was vacuum filtered. in thisway, 0.84 gm of l7a-ethynyl-19-nortestosterone were obtained. Theproduct had a melting point of 206C. and a specific rotation [a] -22.5(c 2 percent in chloroform).

After havingbeen purified, a sample of this product had a melting pointof 206.5 to 207C and a specific rotation [a] -24 2' (c 1 percentinchloroform) and was found to be identicalto a sample of17aethynyl-19-nor-testosterone prepared according to a different method.

EXAMPLE V1 Preparation ofv l7o'r-ethyll'9-nor-testosterone Step A:

Preparation of 3,5-bis-(ethylenedioxy)-l7a-ethyl- 4,5-seco-estrane- 173-01 30 cc of toluene and cc of ethanol containing 0.2 percent ofpyridine were introduced into a hydrogenation vessel, then 3 gm of3,5-bis-(ethylenedioxy)-l7aethynyl-4,5-seco-estrane-l713-01 (describedin Step A- of Example V) and finally 1.2 gm of palladizedtalc containing2 percent of palladiumwere added. The apparatus was purged, and themixture therein was agitated under an atmosphere ofhydrogen until thecom- 10.7 cc of toluene, 4.3 cc of methanol and 4.3 cc of water. Thesolution was heated to reflux and 2.13 gm of citric acid monohydratewere added. Then the solution was maintained at reflux for 1 hour;thereafter 10.7 cc

of water were added. Next, the solution was concen- 1,708 cm: carbonyl3,600 cm: hydroxyl This product is not described in the literature. StepC:

Obtention of l7a-ethyll 9-nor-testosterone 1.35 gm ofl7a-ethyl-4,5-seco-estrane-176-0135- dione were dissolved in 7 cc ofmethanol, and 0.236 gm of sodium methylate were added thereto. Next, thesolution was agitated for 5 hours :atroom temperature and thereafterneutralized by the addition of acetic acid. The methanol was distilledtherefrom under reduced pressure. Water was added and the insolubleportion of the. reaction mixture was extracted with methylene chloride.The methylene chloride solution was dried over magnesium-sulfate andconcentrated to dryness under reduced pressure. The resultant residue'was purified by trituration with ethyl ether, and 0.557

gm of 17a-ethyll 9-nor-testostero ne was obtained. The product had amelting point of 136C and a specific rotation of [at] +21 i 0.5 (c 2percent in methanol). Ultraviolet spectra (in ethanol) max. at 240 to241 my. 6 16,450

This product was identical to 17a-ethyll 9-nortestosterone preparedaccording to a different method.

EXAMPLE V11 Preparation of the acetate 0f 17a-ethynyll9-nor-testosterone' Step A:

Preparation of 3,5-bis-(ethylenedioxy)-17ot-ethynyl- 17-B-acetoxy-4,5-seco-estrane I gm of3,5-bis-(ethylenedioxy)-17or-ethynyl-4,5-

seco-estrane-17fl-ol (described in Step A of.Example estrane. Theproduct had ameltinlg point of 174C and was utilized. as such for thenext step.

A sample of this product, purified for analysis by crystallization frommethanol, had a melting point of 174C and a specific rotation [01] 3l.5i 1 1 percent in chloroform containing 1% of pyridine) andpossessedthefollowing characteristics: Analysis: C H O molecular weight446.56 Calculated: C 69.92% H 8.59%

Found: 699 8.8 A Infrared spectra (in chloroform): Absorption at:

1,738 cm: carbonyl 3,300 cm: ethynyl I This product is not described inthe literature. Step B:

Preparation of 17a-ethynyll 7B-acetoxy-4,5-secoestrane-3,5-dione 3.2 gmof 3,5-bis-(ethylenedioxy)-l7a-ethynyl-17B- acetoxy-4,5-seco-estranewere introduced-into a mixture of 16 cc of toluene, 6.4 cc of methanoland 6.4 cc of water. Then the reaction mixture was heated to reflux, 3.2gm of citric acid monohydrate were added, and the reaction mixture wasmaintained at reflux for 15 hours. Thereafter, 16 cc of water were addedto the reaction mixture, which was then distilled under reduced pressurein order to eliminate the toluene and the methanol. After theprecipitate obtained had been vacuum filtered and dried, 2.58 gm of aproduct were Infrared spectra (in chloroform):

Absorption at:

1,708 cm: carbonyl 1,738 cm: carbonyl of the acetate 3,300 cm": ethynylThis product is not described in the literature. Step C:

Preparation of the 3-pyrrolidyl-l7a-ethynyl-l7B- acetoxy-A -estradiene0.500 gm of l7a-ethynyl-17B-acetoxy-4,5-secoestrane-3,5-dione wereintroduced into cc of methanol; then 0.25 cc of pyrrolidine were added.The mixture was agitated for hours at room temperature and under anatmosphere of nitrogen. The precipitate formed was vacuum. filtered andwashed with methanol, thus obtaining 0.52 gm of3-pyrrolidyl-l7aethynyl-17t3-acetoxy-A -estradiene. The product had amelting point of 186C and a specific rotation [01] 276 :t 4 (c 0.5percent in dimethylformamide). It was utilized as such for the nextstep. Analysis: C H O N; molecular weight 393.55 Calculated: C 79.34% H8.96% N 3.56% Found: 79.1 9.2 3.9

This product Step D:

Preparation of the acetate of l7a-ethynyl-19-nortestosterone 0.285 gm of3-pyrrolidyl-l7a-ethyny1-l7B-acetoxy- A -estradiene were introduced into1.4 cc of '2 N sulis not described in the literature.

furic acid. The mixture was agitated for 15 hours at room temperature:then it'was slowly poured into a mixture of2.8 cc of 2N sodium hydroxidesolution and 5.7 gm of water and ice. Next, the reaction mixture wasagain agitated for 2 hours at 0C., acidified with 9N sulfuric acid toobtain a pH of l, and then again agitated for one hour at 0C. Theprecipitate fromed was vacuum filtered, washed withwater and dried. Thisproduct was twice recrystallized from a water-acetone mixture. 0.154 gmof acetate of l7a-ethynyl-19-nortestosterone was obtained. The producthad a melting point of 163C and a specific rotation [at] 28.5 i 1percent (0 1 percent in chloroform). [t was identical to a sample of theacetate of l7a-ethynyl-19-nortestosterone prepared according to adifferent process.

EXAMPLE Vlll Preparation of 17a-ethynyl-A'-estradiene-17B-o1-3-one StepA: Preparation of 3,5-bis-(ethylenedioxy)-17a-ethynyl-4,5-seco-A-estrene- 1 713-01 Underan atmosphere of nitrogen, 2.6 gm ofpotassium were introduced into a mixture of 26.4 cc of tert. amylalcohol and 10.4 cc of benzene. The mixture was heated to 55C to 60C andmaintained at this temperature for 1 hour while agitating. Then a streamof acetylene was allowed to bubble through the reaction solution forthou and 30 minutes at a temperature of 55 and 60C. Thereafter, thereaction solution was cooled to room temperature and, while maintainingthe bubbling of acetylene therethrough, a solution of 500 mg of3,5-bis-(ethylenedioxy)-4,5-seco-A -estrenel7-one (described in Step Cof Example 1V) in a mixture of 10.4 cc of benzene and 10.4 cc of ethylether was introduced into the reaction solution. The reaction mixturewas then agitated for twohours while acetylene continued to be bubbledtherethrough. Next, water was added to the reaction mixture. The organicphase was separated by decanting, washed with water, dried andconcentrated to dryness under reduced pressure.

The residue was triturated with isopropyl ether and then crystallizedfrom the same solvent. In this manner 350 mg of3,5-bis-(ethylenedioxy)-l7a-ethynyl-4,5- seco-A-estrene-l7B-ol wereobtained, having a melting point of 152C.

A sample of this product was purified for analysis by crystallizationfirst from isopropyl ether, then from aqueous methanol. The product hada melting point of 152C with a specific rotation [a} =-21.5 (c 0.5percent in methanol). Analysis: C H O molecular weight 402.51Calculated: C 71.61% H 8.51% Found: 71.5 8.4

This product is not described in the literature.

'Step B.

Preparation of l7a-ethynyl-4,5-seco-A -estrene-17B- ol-3,5dione Under anatmosphere of nitrogen, 6 gm of 3,5 -bis- (ethylenedioxy)-17a-ethynyl-4,5-seco-A l"-estrenel7B-ol were introduced into amixture of 30 ccof toluene and 12cc of methanol. Then 12 cc of waterwere added to the mixture, which was then brought to reflux whileagitating. 6 gm of citric acid were added and the reaction mixture wasmaintained at reflux for one hour.

Thereafter, 30 cc of water were added and the methanol and toluene wereeliminated under reduced pressure. The aqueous phase was extracted withmethylene chloride. The extracts were combined and the organic solutionobtained was washed with water, dried and finally concentrated todryness under reduced pressure.

The residue was admixed with ether. The precipitate formed was isolatedby being vacuum filtered, and the mother liquors, which will be referredto hereinafter as Solution A, were preserved. The product obtained waspurified by crystallization from ether and 0.99 gm ofl7oz-ethynyl-4,5-seco-A -estrene-17B-ol-3,5-dione was obtained having amelting point of 124C.

A sample of this product was recrystallized from ether and had a meltingpoint of 124C with a specific rotation [a] 73 (c 0.65 percent inmethanol).

Analysis: C H O molecular weight 314.41 Calculated: C 76.40% H 8.33%

Found: 76.2 8.4

Ultraviolet spectra (in ethanol):

A max. at 248 to 249 my. 6 15,000

This product is not described in the literature.

Moreover, by starting with the Solution A maintained at C for severalhours, a precipitate was obtained. This precipitate was vacuum filteredand purified by crystallization from ethyl ether. In this manner, 210 mgof l7a-ethynyl-4,5-seco A -estrene-l7B-ol- 3,5-dione were obtained. Theproduct had a melting point of 143C and a specific rotation [a] =l (c0.55 percent in methanol). Analysis: C H O molecular weight 314.41Calculated: C 76.40% H 8.33%

Found: 76.4 8.2

By employing the conventional processes of ketalization, this compoundwas coverted into 3,5-bis- (ethylenedioxy 1 7a-ethynyl-4,5-seco-A-estrene- 17B-ol, which could be utilized again.

This product is not described in the literature.

Step C:

Preparation of l7a-ethynyl-A-estradiene-l7/3-01- 3-one Under an inertatmosphere, 0.600 gm of 17aethynyl-4,5-seco-A -estrene-l7B-ol-3,5-dionewere in troduced into 2.2 cc of benzene. Then, while maintaining thetemperature between 0C and +3C., 1.4 cc of a solution of sodiumtert.-amylate in toluene, containing 2.45 gm of sodium per 100 cc, wasadded in the space of 20 minutes. While maintaining the previouslyrecited temperature, the reaction mixture was agitated for 2 hours.Thereafter, first 1 cc of benzene, then a mixture of 0.3 cc oftert.-butyl alcohol and 0.5 cc of benzene were added to the reactionmixture. The temperature was elevatedto 20C and the'reaction mixture wasagitated for one hour at this temperature. The pH was adjusted to 7 bythe addition of a benzenic solution of acetic acid. Next, the reactionmixture was agitated for 45 minutes and then water was added. Thesolvents were eliminated under reduced pressure. The precipitate formedwas vacuum filtered, washed and dried. 570 mg of product were obtained,having a melting point of 178C.

This product was purified by crystallization from ethyl acetate, thusobtaining 416 mg of l7o -ethynyl- A '-estradiene-l7B-ol-3-one. Theproduct had a melting point of 183C and a specific rotation [a] ,3 I 355(c 0.2 percent in methanol). Ultraviolet spectra (in ethanol): max atmp. e 5,850 lnflection toward 235 to 236 mu. 5 4,590 lnflection toward247 my. 6 3,550 max at 304 m,u e 20,000

The preceding specific embodimentsare illustrative of the process of theinvention. 1t is to be understood, however, that other expedients knownto those skilled in the art can be employed without departing from thespirit of the invention or the scope of the appended claims.

We claim:

1. 3,5-diketals of l3fl-alkyl-l7oz-R 'l7/3-OR-4,5-seco-gonane-3,5-diones of the formula phenylalkanoic acids,phenoxyallxanoic acids, furane- 2-carboxy1ic acids, nicotinic acids andfi-keto-alkanoic acids; R is an alkyl having from one to four carbonatoms selected from the group consisting of methyl, ethyl, n-propyl andn-butyl, R is a member selected from the group consisting of loweralkyl, of l-7 carbon atoms lower alkenyl, and lower alkynyl, of 2-7carbon atoms X represents a member selected from the group consisting ofarid \R,

wherein R is a lower alkyl and R' is selected from the group consistingof lower alkyleneand (6-methylbenzyl)-ethylene; and A is selected fromthe group consisting of two hydrogens and a double bond.

2. The compound of claim 1 wherein R is hydrogen, R is methyl, R" isethynyl, X is ethylenedioxy and A is two hydrogens.

3. The compound of claim 1 wherein R is hydrogen R is methyl, R isethyl, X is ethylenedioxy and A is two hydrogens.

4. The compound of claim 1 wherein R is acetoxy, R is methyl, R" isethynyl, X is ethylenedioxy and A is two hydrogens.

5. The compound of claim 1 wherein R is hydrogen, R ismethyL-R isethynyl, X is ethylenedioxy and A is a double bond. r

PCP-1050 Inventor-(s) Pitnt 3, 8 3 686 Dated October 22, 197A JulienWarnarifi, Jean Jolly and Robe'rt Joly It is certified that errorappears in the above-identified patent EN TEE PATENT Cplumri Line.

' [SEAL] Attest:

RUTH C. MASON Arresting Officer and that said Letters Patent are herebycorrected as shown below:

afterlines startingfOJ insert [3o] FOREIGN ARELICATION P IOR I'JJY DATAI ia j26,*196 jrrar ie 63,0861.

Signed and seal! second Day of Dacembarl975 C. MARSHALL DARKCommissioner oflatems and Trademarks

1. 3,5-DIKETALS OF 13B-ALKYL-17A-RIV.17B-OR-4,5-SECOGONANE-3,5-DIONES OFTHE FORMULA
 2. The compound of claim 1 wherein R is hydrogen, R'' ismethyl, Riv is ethynyl, X is ethylenedioxy and A is two hydrogens. 3.The compound of claim 1 wherein R is hydrogen R'' is methyl, Riv isethyl, X is ethylenedioxy and A is two hydrogens.
 4. The compound ofclaim 1 wherein R is acetoxy, R'' is methyl, Riv is ethynyl, X isethylenedioxy and A is two hydrogens.
 5. The compound of claim 1 whereinR is hydrogen, R'' is methyl, Riv is ethynyl, X is ethylenedioxy and Ais a double bond.